Structure-based virtual screening of novel, high-affinity BRD4 inhibitors

Area of Science:

• Computational chemistry
• Drug discovery
• Molecular biology

Background:

• Bromodomains (BRDs) are key protein modules involved in gene regulation.
• BRD4 is a significant therapeutic target for various cancers, including leukemia and lymphoma.
• Existing BRD4 inhibitors like (+)JQ1 have toxicity concerns, necessitating new drug development.

Purpose of the Study:

• To virtually screen compound databases for novel BRD4 inhibitors targeting the Kac binding site.
• To evaluate the efficacy and safety of identified compounds using computational simulations.
• To explore the potential of steered molecular dynamics in designing new therapeutic agents.

Main Methods:

• Virtual screening and molecular docking against BRD4's Kac binding site.
• Molecular dynamics simulations and MM-PB/GBSA binding free energy calculations.
• Steered molecular dynamics (SMD) simulations to analyze inhibitor-target interactions.

Main Results:

• Identified 11 novel BRD4 inhibitors with binding energies superior to (+)JQ1.
• Compounds ZINC01411240, ZINC19632618, and ZINC04818522 emerged as potential drug candidates.
• Demonstrated a strong correlation between SMD simulation results and MM-PBSA/GBSA binding free energies.

Conclusions:

• The identified compounds represent promising leads for developing safer BRD4-targeted therapies.
• Steered molecular dynamics is a valuable tool for designing effective new inhibitors.
• This study provides a computational framework for future drug discovery efforts against BRD4.